Veliparib in Combination With Carboplatin for the Treatment of Triple Negative Breast Cancer

ABSTRACT

The invention relates to a method for the treatment of triple negative breast cancer in a subject, comprising administering to the subject an effective amount of 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide, or a pharmaceutically acceptable salt thereof, and an effective amount of carboplatin, in combination with standard of care.

This application is a continuation of U.S. patent application Ser. No.15/276,345 filed on Sep. 26, 2016, which is a continuation of U.S.patent application Ser. No. 14/565,645 filed on Dec. 10, 2014, now U.S.Pat. No. 9,486,466 issued on Nov. 8, 2016, which claims priority to U.S.Provisional Patent Application No. 61/914,216 filed on Dec. 10, 2013,all of which are incorporated herein by reference.

FIELD OF THE INVENTION

This invention pertains to the use of veliparib and carboplatin in thetreatment of subjects with triple negative breast cancer.

BACKGROUND OF THE INVENTION

Invasive breast carcinoma is a group of malignant epithelial tumorscharacterized by invasion of adjacent tissues and a marked tendency tometastasize to distant sites. Breast cancer exhibits a wide range ofmorphological phenotypes and specific histopathological types that haveparticular prognostic and clinical characteristics. For example,subtypes are stratified according to their estrogen receptor (ER),progesterone receptor (PR) and human epidural growth factor receptor(HER2) status. For many patients, targeted therapies against one of thereceptor targets are available. However, 10-20% of mammary tumors lackhormone receptors (ER/PR) and do not overexpress Her2/neu protein,clinically defined as triple negative breast cancer.

Triple negative breast cancers are more aggressive than ER/PR+ tumors orHer2+ tumors, and there are no targeted therapies available for thisdisease. The use of an anthracycline, taxane, and an alkylating agent isrecommended. However, a large number of patients treated withchemotherapy and surgery for early breast cancer (EBC) are not cured oftheir disease. Approximately 30% to 40% of patients with TNBC will havea recurrence of disease within 3 to 10 years of treatment withneoadjuvant therapy and surgery. Most patients with recurrent diseasewill die from their breast cancer. Therefore, identification oftherapeutic advances is critical.

Poly (ADP-ribose) polymerase (PARP) is a nuclear enzyme that recognizesDNA damage and facilitates DNA repair. PARP activity is required for therepair of single-stranded DNA breaks through the base excision repairpathways. Cancer cells are often deficient in double-stranded DNA-repaircapability, and are therefore more dependent on PARP directedsingle-stranded DNA-repair than are normal cells. Consequently,inhibition of PARP enhances the anti-tumor effects of DNA-damagingagents in many cancer cells.

Most early breast cancers are treated with multi-modality therapy(surgery+/−radiotherapy+chemotherapy). Multiple large randomized trialshave demonstrated identical outcomes may be obtained irrespective of theorder of surgery and chemotherapy. Thus neoadjuvant (chemotherapyfollowed by surgery) and adjuvant (surgery followed by chemotherapy)treatment regimens are considered equivalent. One advantage ofneoadjuvant therapy is that tumor responses to chemotherapy can bemeasured, unlike in the adjuvant setting where all known tumor issurgically removed prior to chemotherapy. The tumor response toneoadjuvant chemotherapy provides significant prognostic information.Those patients that achieve complete pathological tumor responses (noliving cancer cells can be identified in the surgical specimen) havesignificantly better prognoses than those that do not.

It has been discovered that the PARP inhibitor veliparib,2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide, actssynergistically in combination with the DNA-damaging agent carboplatinto increase the efficacy of the current standard-of-care treatment forearly triple negative breast cancer. Adding veliparib and carboplatin tothe standard of care increases the number of women that achieve pCRstatus in a neoadjuvant setting. This is estimated to translate intoadditional treated women remaining free of disease at 5 years. This isalso expected increase the number of patients who would become eligiblefor less extensive surgery (fewer mastectomies, more breast-conservingsurgery).

BRIEF SUMMARY OF THE INVENTION

The present invention relates to a method for the treatment ofER-negative, PR-negative, and HER-2 negative cancer of the breast in asubject, comprising administering to the subject 50 mg of2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide twice aday continuously for twelve weeks; 80 mg/m² paclitaxel on day 1 oftwelve 7-day cycles; and AUC 6 mg/mL/min carboplatin on day 1 of four21-day cycles.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The terms “treat”, “treating” and “treatment” refer to a method ofalleviating or abrogating a disease and/or its attendant symptoms.

By “pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The “subject” is defined herein to include animals such as mammals,including, but not limited to, primates (e.g., humans), cows, sheep,goats, horses, dogs, cats, rabbits, rats, mice and the like. Inpreferred embodiments, the subject is a human.

“Effective amount” or a “pharmaceutically-effective amount” in referenceto 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamiderefers to the amount sufficient to induce a desired biological,pharmacological, or therapeutic outcome in a subject.

Triple negative breast cancer (TNBC) is defined by the absence ofestrogen receptor (ER), progesterone receptor (PR), and HER2/neuoverexpression.

Pathological Complete Response (pCR) is the absence of any residualinvasive cancer on hematoxylin and eosin evaluation of the resectedbreast specimen and any resected lymph node tissue following completionof neoadjuvant systemic therapy.

Breast Conservation Rate (BCR) is the rate of eligibility for breastconservation after neoadjuvant therapy among subjects for whommastectomy was planned diagnosis.

Event Free Suvival (EFS) is defined as the time from random assignmentto the document of the first of the following events: failure to reachpotential curative surgery; local regional, or distance recurrence ofbreast cancer following curative surgery; a new breast cancer; anothernew onset malignancy, or death as a result of any cause.

Overall Survival (OS) is defined as the number of days from the day thesubject is randomized to the date of the subject's death.

Clinical Response Rate (CRR) is defined as the proportion of subjectswith complete or partial response as determined by imaging. For example,CR and PR can be assessed by MRI after a period of therapy (such as 12weeks) and categorized according to percent reduction in tumor size.

Residual Cancer Burden is a numerical index of four classes to measureresidual disease by combining histopathologic components of residualdisease (cellularity, overall diameter, number and extent of nodalinvolvement). Subjects with RCB=0 are classified pCR.

Early-stage breast cancer is cancer has not spread beyond the breast orthe axillary lymph nodes.

Primary Tumor Categories

T1: Tumor is 2 cm (¾ of an inch) or less across.

T2: Tumor is more than 2 cm but not more than 5 cm (2 inches) across.

T3: Tumor is more than 5 cm across.

T4: Tumor of any size growing into the chest wall or skin.

Nearby Lymph Nodes

N0: Cancer has not spread to nearby lymph nodes.

N1: Cancer has spread to 1 to 3 axillary (underarm) lymph node(s),and/or tiny amounts of cancer are found in internal mammary lymph nodes(those near the breast bone) on sentinel lymph node biopsy.

N2: Cancer has spread to 4 to 9 lymph nodes under the arm, or cancer hasenlarged the internal mammary lymph nodes (but not both).

The present invention provides a method for the treatment of triplenegative breast cancer in a subject, comprising administering to thesubject an effective amount of veliparib, or a pharmaceuticallyacceptable salt thereof, in combination with an effective amount ofcarboplatin, in addition to standard of care.

According to current guidelines, standard of care chemotherapy shouldcontain anthracyclines and taxanes. Multiple combinations and schedulesthat are recommended include concurrent or sequential anthracyclines andtaxanes. Among the commonly used regimens is doxorubicin andcyclophosphamide followed by paclitaxel or the same combination given inreverse sequence.

In the present invention, the subject has ER-negative, PR-negative, andHER-2 negative (triple-negative) cancer of the breast. Triple negativetumors are defined as:

For ER- and PR-negative: less than or equal to 1% tumor staining byimmunohistochemistry.

For HER-2 negative, defined as IHC 0-1+OR HER2-neu negative according toASCO-CAP guideline recommendations.

In another embodiment, the subject has a diagnosis of a BRCA1 and/or aBRCA2 mutation. The mutation may be a deleterious mutation. The mutationmay be a germline mutation or a somatic mutation.

In one embodiment, the subject has early-stage breast cancer. In oneembodiment, the subject has clinical stage T2-4 NO-2 or Ti N1-2 invasivebreast cancer. The subject may have multiple lesions, e.g., up to 2. Inanother embodiment, the subject is a candidate for potentially curativesurgery.

In one embodiment, the subject has definitive breast surgery, eithermastectomy or breast conserving surgery. The chemotherapy of theinvention may be adjuvant therapy (surgery followed by chemotherapy) orneoadjuvant therapy (chemotherapy followed by surgery). In the case ofneoadjuvant therapy, breast surgery is performed approximately 4 to 8weeks after the subject's last dose.

2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide is aninhibitor of poly(ADP-ribose)polymerase (PARP) and has been previouslydescribed in WO 2006-110816. Poly(ADP-ribose)polymerase has an essentialrole in facilitating DNA repair, controlling RNA transcription,mediating cell death, and regulating immune response. These actions makePARP inhibitors targets for a broad spectrum of disorders. (Virag L., etal., Pharmacol. Rev. 2002 54(3):375-429). In various preclinical cancermodels and human clinical trials, PARP inhibitors have been shown topotentiate radiation and chemotherapy by increasing apoptosis of cancercells, limiting tumor growth, decreasing metastasis, and prolonging thesurvival of tumor-bearing subjects. (WO 2007-084532; Donawho C. K., etal., Clin Cancer Res 2007 13(9):2728-37; Kummar S., et al., J ClinOncol. 2009 27(16):2705-11).

This invention also is directed, in part, to all salts of2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide andmethods of their use. A salt of a compound may be advantageous due toone or more of the salt's properties, such as, for example, enhancedpharmaceutical stability in differing temperatures and humidities, or adesirable solubility in water or other solvents. Where a salt isintended to be administered to a patient (as opposed to, for example,being in use in an in vitro context), the salt preferably ispharmaceutically acceptable and/or physiologically compatible. The term“pharmaceutically acceptable” is used adjectivally in this patentapplication to mean that the modified noun is appropriate for use as apharmaceutical product or as a part of a pharmaceutical product.Pharmaceutically acceptable salts include salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. In general, these salts typically may be prepared by conventionalmeans by reacting, for example, the appropriate acid or base with acompound of the invention.

Pharmaceutically acceptable acid addition salts of2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide can beprepared from an inorganic or organic acid. Examples of often suitableinorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric,carbonic, sulfuric, and phosphoric acid. Suitable organic acidsgenerally include, for example, aliphatic, cycloaliphatic, aromatic,araliphatic, heterocyclic, carboxylic, and sulfonic classes of organicacids. Specific examples of often suitable organic acids includeacetate, trifluoroacetate, formate, propionate, succinate, glycolate,gluconate, digluconate, lactate, malate, tartaric acid, citrate,ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate,glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate,p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate),ethanesulfonate, benzenesulfonate, pantothenate,2-hydroxyethanesulfonate, sulfanilate, cyclohexylaminosulfonate, algenicacid, beta-hydroxybutyric acid, galactarate, galacturonate, adipate,alginate, bisulfate, butyrate, camphorate, camphorsulfonate,cyclopentanepropionate, dodecyl sulfate, glycoheptanoate,glycerophosphate, heptanoate, hexanoate, nicotinate, oxalate, palmoate,pectinate, 2-naphthalesulfonate, 3-phenylpropionate, picrate, pivalate,thiocyanate, tosylate, and undecanoate.

Pharmaceutically acceptable base addition salts of2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide include,for example, metallic salts and organic salts. Preferred metallic saltsinclude alkali metal (group Ia) salts, alkaline earth metal (group IIa)salts, and other physiologically acceptable metal salts. Such salts maybe made from aluminum, calcium, lithium, magnesium, potassium, sodium,and zinc. Preferred organic salts can be made from amines, such astromethamine, diethylamine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine), and procaine. Basic nitrogen-containing groups canbe quaternized with agents such as lower alkyl (C₁-C₆) halides (e.g.,methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides),dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamylsulfates), long chain halides (e.g., decyl, lauryl, myristyl, andstearyl chlorides, bromides, and iodides), arylalkyl halides (e.g.,benzyl and phenethyl bromides), and others.

This invention also is directed, in part, to all compositions of2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide andmethods of their use.2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide may beadministered with or without an excipient. Excipients include, but arenot limited to, encapsulators and additives such as absorptionaccelerators, antioxidants, binders, buffers, coating agents, coloringagents, diluents, disintegrating agents, emulsifiers, extenders,fillers, flavoring agents, humectants, lubricants, perfumes,preservatives, propellants, releasing agents, sterilizing agents,sweeteners, solubilizers, wetting agents, mixtures thereof and the like.

Excipients for preparation of compositions comprising2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide to beadministered orally include, but are not limited to, agar, alginic acid,aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butyleneglycol, carbomers, castor oil, cellulose, cellulose acetate, colloidalsilica, cocoa butter, corn starch, corn oil, cottonseed oil,cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate,ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol,groundnut oil, hydroxypropylmethyl celluose, isopropanol, isotonicsaline, lactose, magnesium hydroxide, magnesium stearate, malt,mannitol, microcrystalline cellulose, monoglycerides, olive oil, peanutoil, potassium phosphate salts, potato starch, povidone, propyleneglycol, Ringer's solution, safflower oil, sesame oil, sodiumcarboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate,sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose,surfactants, talc, titanium dioxide, tragacanth, tetrahydrofurfurylalcohol, triglycerides, water, mixtures thereof and the like.

In one embodiment of the invention, the dose of veliparib, or apharmaceutically acceptable salt or solvate thereof, is 50 mg twice aday continuously for twelve weeks (first segment).

Also during the first segment, carboplatin is administered intravenouslyat a dose of AUC 6 mg/mL/min on Day 1 of four 21-day cycles.

Also during the first segment, paclitaxel is administered intravenouslyat a dose of 80 mg/m² on Day 1 of twelve weekly cycles.

In another embodiment of the invention, the first segment is followed bya second chemotherapy segment. In the second segment, 60 mg/m² ofdoxorubicin will be administered intravenously on Day 1 of four 14 daycycles, and 600 mg/m² of cyclophosphamide will be administeredintravenously on Day 1 of four 14 days cycles. Alternatively, 60 mg/m²of doxorubicin will be administered intravenously on Day 1 of four 21day cycles, and 600 mg/m² of cyclophosphamide will be administeredintravenously on Day 1 of four 21 days cycles.

The dose of veliparib may be delayed at any time during the firstsegment due to toxicity and resumed at the starting dose.

Likewise, the dose of carboplatin and/or the dose of paclitaxel may beindependently delayed at any times during the first segment due totoxicity and resumed at the starting dose. If both carboplatin andpaclitaxel are delayed, then2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide is alsodelayed. In the case of delays, the period of the first segment may betwelve weeks, thirteen weeks, fourteen weeks, fifteen weeks, or sixteenweeks. The period of the first segment may not exceed sixteen weeks. Ifthe first segment extends through sixteen weeks, the first segment isdiscontinued and the second segment commences.

Alternatively, the dose of veliparib, paclitaxel, carboplatin,doxorubicin, and/or cyclophosphamide may be reduced. Reductions in doselevel are show in Table 1. Once dose levels are decreased, they are notre-escalated.

TABLE 1 Carbo- Pacli- Doxoru- Cyclophos- Dose level platin taxel bicinphamide Veliparib Starting AUC 6 80 mg/m² 60 mg/m² 600 mg/m² 50 mg DoseLevel Dose Level - AUC 5 70 mg/m² 50 mg/m² 500 mg/m² 40 mg 1 DoseLevel - AUC 4 60 mg/m² 40 mg/m² 400 mg/m² N/A 2

Other PARP inhibitors are known in the art, incluing olaparib, BMN 673,rucaparib, iniparib, INO-1001, E7016, CEP-9722, AZD2461, MK-4827, andJP-289.

These other PARP inhibitors can also be combined with platins in a firstsegment in addition to the standard of care.

Suitable doses for a PARP inhibitor in the first segment are 5 mg/day to250 mg/day. Alternatively, suitable doses for a PARP inhibitor in thefirst segment are 10 mg/day to 150 mg/day. Alternatively, suitable dosesfor a PARP inhibitor in the first segment are 25 mg/day to 100 mg/day.Suitable doses include 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, 25mg/day, 30 mg/day, 35 mg/day, 40 mg/day, 50 mg/day, 55 mg/day, 60mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90mg/day, 95 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, 200mg/day, 210 mg/day, 220 mg/day, 230 mg/day, 240 mg/day, or 250 mg/day.

In the case of neoadjuvant therapy of a first segment and a secondsegment of the invention, the subject may have a pathological completeresponse (pCR). pCR is defined as the absence of any residual invasivecancer on hexatoxylin and eosin evaluation of the resected breastspecimen and any resected lymph node tissue following completion ofneoadjuvant therapy.

Also in the case of neoadjuvant therapy of a first segment and a secondsegment of the invention, the subject may be eligible for breastconservation even though a mastectomy was planned at diagnosis.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention.Variations of those preferred embodiments may become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventors expect skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than as specifically described herein. Accordingly, thisinvention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

EXAMPLE Example 1

This example is a Phase 2, interventional, randomized, open label studyevaluating the safety and efficacy of veliparib and carboplatinadministered concurrently with standard chemotherapy in subjects withearly-stage triple negative breast cancer.

Inclusion Criteria

Female

Patients with histologically confirmed invasive cancer of the breast.

Clinically or radiologically measureable disease in the breast afterdiagnostic biopsy, defined as longest diameter greater than or equal to25 mm (2.5 cm).

No prior cytotoxic regimens are allowed for this malignancy. Patientsmay not have had prior chemotherapy or prior radiation therapy to theipsilateral breast for this malignancy. Prior bis-phosphonate therapy isallowed.

Age ≥18 years.

ECOG performance status 0-1.

Willing to undergo core biopsy of the primary breast lesion to assessbaseline biomarkers.

Non-pregnant and non-lactating.

No ferromagnetic prostheses. Patients who have metallic surgicalimplants that are not compatible with an MRI machine are not eligible.

Ability to understand and willingness to sign a written informedconsent.

Eligible tumors must meet one of the following criteria: Stage II orIII, or T4, any N, MO, including clinical or pathologic inflammatorycancer or Regional Stage IV, where supraclavicular lymph nodes are theonly sites metastasis.

Any tumor ER/PgR status, any HER-2/neu status as measured by localhospital pathology laboratory and meets any tumor assay profiledescribed in protocol section 4.1.2F.

Normal organ and marrow function: Leukocytes ≥3000/μL, Absoluteneutrophil count ≥1500/μL, Platelets ≥100,000/μL, Total bilirubin withinnormal institutional limits, unless patient has Gilbert's disease, forwhich bilirubin must be ≤2.0×ULN, AST(SGOT)/ALT (SGPT)≤1.5×institutionalULN, creatinine ≤1.5×institutional ULN.

No uncontrolled or severe cardiac disease. Baseline ejection fraction(by nuclear imaging or echocardiography) must by >50%.

No clinical or imaging evidence of distant metastases by PA and LateralCXR, Radionuclide Bone scan, and LFTs including total bilirubin, ALT,AST, and alkaline phosphatase.

Tumor assay profile must include on of the following: MammaPrint High,any ER status, any HER2 status, or MammaPrint Low, ER negative (≤5%),any HER2 status, or MammaPrint Low, ER positive, HER2/neu positive byany one of the three methods used (IHC, FISH, TargetPrint™).

Exclusion Criteria

Use of any other investigational agents within 30 days of starting studytreatment.

History of allergic reactions attributed to compounds of similarchemical or biologic composition to the study agent or accompanyingsupportive medications.

Uncontrolled intercurrent illness including, but not limited to, ongoingor active infection, symptomatic congestive heart failure, unstableangina pectoris, cardiac arrhythmia, or psychiatric illness/socialsituations that would limit compliance with study requirements.

Dosing

Patients received 50 mg po bid during the 12 weekly treatment cyclespost-randomization and carboplatin: AUC 6 IV every three weeks for fourweeks during the 12 weekly treatment cycles post-randomization withstandard chemotherapy or alternatively standard chemotherapy alone.Standard chemotherapy was paclitaxel: 80 mg/m² IV during the 12 weeklytreatment cycles post randomization; doxorubicin: 60 mg/m² IV aftercompletion of the 12 weekly treatment cycles and prior to surgery forweeks 13-16; cyclophosphamide: 600 mg/m² IV after completion of the 12weekly treatment cycles and prior to surgery for weeks 13-16.

Efficacy

Primary Outcome Measure

Determine whether adding veliparib and carboplatin to standardneoadjuvant medications increases the probability of pathologic completeresponse (pCR) over standard neoadjuvant chemotherapy for triplenegative breast cancer.

Secondary Outcome Measures

Establishing predictive and prognostic indices based on qualificationand exploratory markers to predict pCR and residual cancer burden (RCB).

To determine three- and five-year relapse-free survival (RFS) and OSamong the treatment arms. [Time Frame: Three- and Five-Year Post-surgeryFollow-up].

To determine incidence of adverse events (AEs), serious adverse events(SAEs), and laboratory abnormalities of each investigational agenttested. [Time Frame: Post-Randomization, Pre-AC, Pre-Surgery,Post-Surgery up to One Year during follow-up].

22 subjects received standard chemotherapy followed by surgery (control)while 39 patients received veliparib and carboplatin in addition tostandard chemotherapy followed by surgery.

TABLE 2 pCR % Control arm 23% (n = 22) Veliparib arm 56% (n = 39)

What is claimed is:
 1. A method for the treatment of BRCA breast cancerin a subject, comprising administering to the subject in need thereof afirst chemotherapy segment comprising administering a therapeuticallyeffective amount of2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide.
 2. Themethod of claim 1, wherein the therapeutically effective amount of2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide isadministered twice a day continuously for twelve weeks.
 3. The method ofclaim 2, wherein 40 mg-125 mg of2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide isadministered to the subject twice a day continuously for twelve weeks.4. The method of claim 3, wherein 50 mg of2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide isadministered to the subject twice a day continuously for twelve weeks.5. The method of claim 1, wherein administering to the subject in needthereof a first chemotherapy segment comprising administering (a) atherapeutically effective amount of paclitaxel; and (b) atherapeutically effective amount of carboplatin.
 6. The method of claim5, wherein the therapeutically effective amount of paclitaxel isadministered on day 1 of twelve 7-day cycles.
 7. The method of claim 5,wherein the therapeutically effective amount of carboplatin isadministered on day 1 of four 21-day cycles.
 8. The method of claim 6,wherein 80 mg/m² paclitaxel is administered on day 1 of twelve 7-daycycles.
 9. The method of claim 7, wherein area under the curve (AUC) 6mg/mL/min carboplatin is administered on day 1 of four 21-day cycles.10. The method of claim 1, wherein the first chemotherapy segment isfollowed by a second chemotherapy segment comprising administering tothe subject (a) 60 mg/m² doxorubicin on day 1 of four 14-day cycles; and(b) 600 mg/m² cyclophosphamide on day 1 of four 14-day cycles.
 11. Themethod of claim 1, wherein the first chemotherapy segment is followed bya second chemotherapy segment comprising administering to the subject(a) 60 mg/m² doxorubicin on day 1 of four 21-day cycles; and (b) 600mg/m² cyclophosphamide on day 1 of four 21-day cycles.
 12. The method ofclaim 1, wherein the subject has early-stage breast cancer.
 13. Themethod of claim 1, wherein the subject is a candidate for surgery. 14.The method of claim 13, wherein the subject has surgery approximately4-8 weeks after the last chemotherapy treatment.
 15. The method of claim14, wherein the subject has a mastectomy.
 16. The method of claim 14,wherein the subject has breast conservation surgery.
 17. The method ofclaim 1, wherein the BRCA breast cancer has a BRCA1 mutation.
 18. Themethod of claim 1, wherein the BRCA breast cancer has a BRCA2 mutation.19. A method for the treatment of BRCA breast cancer in a subject,comprising administering to the subject in need thereof a firstchemotherapy segment comprising administering (c) 40 mg-125 mg of2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide twice aday continuously for twelve weeks; (d) 80 mg/m² paclitaxel on day 1 oftwelve 7-day cycles; and (e) area under the curve (AUC) 6 mg/mL/mincarboplatin on day 1 of four 21-day cycles.
 20. The method of claim 19,wherein 50 mg of2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide isadministered to the subject twice a day continuously for twelve weeks.21. The method of claim 19, wherein the first chemotherapy segment isfollowed by a second chemotherapy segment comprising administering tothe subject (c) 60 mg/m² doxorubicin on day 1 of four 14-day cycles; and(d) 600 mg/m² cyclophosphamide on day 1 of four 14-day cycles.
 22. Themethod of claim 19, wherein the first chemotherapy segment is followedby a second chemotherapy segment comprising administering to the subject(c) 60 mg/m² doxorubicin on day 1 of four 21-day cycles; and (d) 600mg/m² cyclophosphamide on day 1 of four 21-day cycles.
 23. The method ofclaim 19, wherein the subject has early-stage breast cancer.
 24. Themethod of claim 19, wherein the subject is a candidate for surgery. 25.The method of claim 24, wherein the subject has surgery approximately4-8 weeks after the last chemotherapy treatment.
 26. The method of claim25, wherein the subject has a mastectomy.
 27. The method of claim 25,wherein the subject has breast conservation surgery.
 28. The method ofclaim 19, wherein the BRCA breast cancer has a BRCA1 mutation.
 29. Themethod of claim 19, wherein the BRCA breast cancer has a BRCA2 mutation.30. A method for the treatment of BRCA breast cancer in a subject,comprising: administering to the subject in need thereof a firstchemotherapy segment and a second chemotherapy segment, the firstchemotherapy segment consisting of a therapeutically effective amount of2-[(2R)-2 methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide andcarboplatin, and the second chemotherapy segment comprising standardchemotherapy comprising doxorubicin, cyclophosphamide, paclitaxel, orcombinations thereof.